Predisposition to phenytoin hepatotoxicity assessed in vitro.
Arene oxide metabolites of phenytoin may be involved in the pathogenesis of drug-induced hepatotoxicity. We examined individual susceptibility to toxicity from such metabolites by exposing human lymphocytes to metabolites generated by a murine hepatic microsomal system. Cells from 17 controls showed no toxicity at concentrations of phenytoin from 31 to 125 microM. Cells from three patients with phenytoin hepatotoxicity manifested dose-dependent toxicity from the metabolites. Phenytoin alone was not toxic to cells. The patients' dose-response curves resembled the response of control cells in which epoxide hydrolase (a detoxification enzyme for arene oxides) was inhibited. Detoxification of non-arene oxide metabolites (e.g., of acetaminophen) was normal in patients' cells. Cells from parents of two patients had intermediate responses. Cells from a sibling of one patient showed no toxicity; a sibling of another patient had a response similar to that of the patient. A heritable defect in response to arene oxides thus may predispose some patients to phenytoin hepatotoxicity.
D000328:Adult; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology; D004198:Disease Susceptibility; D004342:Drug Hypersensitivity / Q000235:genetics* / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D004988:Ethers, Cyclic / Q000378:metabolism; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010672:Phenytoin / Q000009:adverse effects* / Q000378:metabolism
D004988:Ethers, Cyclic; D010672:Phenytoin; D004851:Epoxide Hydrolases